Slit2-ROBO signaling in pericytes and myeloid cells controls vascular development and ocular neovascular disease

项目摘要 周细胞和髓样细胞与内皮细胞合作以协调适当分支的形成， 维持视网膜功能的功能性血管网络，从而实现视觉。通信中断 内皮细胞、周细胞和髓样细胞之间的相互作用导致眼内过度的病理性血管生成， 新生血管性疾病（OND），如晚期年龄相关性黄斑变性和糖尿病视网膜病变， 导致数百万美国人失明。过度的血管生成目前通过抑制单一的 仅靶向内皮细胞的VEGF因子。在该提案中，我们鉴定了一种新的SLIT 2-ROBO 1&2配体- 通过周细胞中的直接受体信号作用促进视网膜新生血管形成的受体途径 和骨髓细胞。通过靶向周细胞和髓样细胞，OND中的ROBO抑制可以赋予额外的细胞毒性。 比单独抑制内皮细胞的VEGF更有效。我们将定义SLIT 2-ROBO 1&2信号传导的分子基础， 它在周细胞和髓样细胞中的生物学作用，以揭示控制视网膜发育的新生物学， 可以应用于OND预防的体内平衡。

PROJECT SUMMARY Pericytes and myeloid cells cooperate with endothelium to orchestrate formation of a properly branched, functional vessel network that sustains retinal function and thereby enables vision. Disrupted communication between endothelium, pericytes and myeloid cells leads to excessive and pathological angiogenesis in ocular neovascular diseases (ONDs) such as advanced age-related macular degeneration and diabetic retinopathy that cause vision loss in millions of Americans. Excessive angiogenesis is currently treated by inhibition of a single factor VEGF that targets endothelial cells only. In this proposal we identify a novel SLIT2-ROBO1&2 ligand- receptor pathway that promotes retinal neovascularization through direct receptor signaling effects in pericytes and myeloid cells. By targeting pericytes and myeloid cells, ROBO inhibition in ONDs may confer additional benefit over VEGF inhibition of ECs alone. We will define the molecular basis of SLIT2-ROBO1&2 signaling and its biological role in pericytes and myeloid cells to uncover novel biology controlling retinal development and homeostasis that could be applied to OND prevention.